Episode 011: Cytopenias Series Pt. 3 - Neutropenia

In our final stop in our Cytopenias series, we discuss the ins and outs of neutropenia. This is another very commonly seen issue in the clinic and in the hospital so most definitely high yield!

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Why is neutropenia dangerous?

• Prone to infections, especially gut translocation of bacteria

Definition of neutropenia:

• NORMAL: WBC 4400-11000 cells/microL; neutrophils make up 40-70% of that

• Neutropenia defined by ANC: WBC (cells/microL) x percent (PMNs  +  bands) ÷ 100 

• Breakdown:

  • Neutropenia: ANC <1500 cells/microL

  • Mild: ANC ≥1000 and <1500 cells/microL

  • Moderate: ANC ≥500 and <1000 cells/microL

  • Severe: ANC <500 cells/microL

  • Agranulocytosis: ANC <200 cells/microL

Approach to workup: HISTORY IS KEY!

• Medications; examples of common culprits-  

  • Chemotherapy 

  • Methimazole 

  • Clozapine 

• Infections

  • Any infections due to bone marrow suppression 

• Toxins 

Less common causes: 

• Congenital

  • Severe congenital neutropenia:

    • Diagnosed in childhood; used to be fatal, but now patients living longer because of G-CSF support

    • 10-30% risk of AML in lifetime

    • Mutations in neutrophil elastase (ELANE) gene or mitochondrial HAX1 gene 

  •  Cyclic neutropenia:

    • Self-limiting neutropenia that occurs every 2-5 weeks

    • Spectrum of symptoms: none or oral ulcers/mild infections

  • Constitutional/ethnic neutropenia:

    • Mild neutropenia (ANC >1000)

    • No history of infections

    • More common in people of Mediterranean and African descent

    • Duffy Antigen Receptor Complex (DARC) gene mutations in patients of African origin

  • Benign Familial:

    • Mild neutropenia

    • Not linked to particular ethnic group

    • Unclear underlying etiology

• Autoimmune

  • Primary autoimmune neutropenia rare in adults

  • Typically secondary autoimmune neutropenia

    • Due to underlying autoimmune disorder

    • Seen with SLE and can worsen with flare of disease

    • Typically mild, seldom needs treatment unless ANC <500

  • Felty syndrome:  

    • Rheumatoid arthritis, splenomegaly, and neutropenia

    • Neutropenia improves with treatment of RA 

• Malignancy

  • Large granular lymphocyte (LGL) leukemia:

    • Often associated with RA and shares features of Felty syndrome (RA, splenomegaly)

    • Caused by monoclonal population of large granular lymphocytes

    • In contrast, in Felty’s: polyclonal or oligoclonal

      • T-cell LGL is more commonly associated with neutropenia

      • Requires treatment with methotrexate or cyclophosphamide

• Dietary

  • B12 and folate rarely cause isolated neutropenia

  • Copper deficiency (gastric bypass): Zinc excess can cause copper deficiencies – ask about denture creams in your history!  

Workup:

• History:

• Prior CBCs

• History of recurrent infections (pneumonia, sinusitis, skin/soft tissue, dental caries)

• Ethnic background

• Family history

• Social history

• Dietary history

• Surgical history (gastric bypass)

Physical exam:

• Adenopathy

• Splenomegaly

• Skin findings suggesting recent ulcers

• Aphthous ulcers

  • example: https://en.wikipedia.org/wiki/Aphthous_stomatitis

Testing:

• CBC with differential

• CMP – assess liver and renal function 

• Peripheral smear

• HIV, Hepatitis serologies

• Special scenarios

• ANA – if autoimmune disease expected

• RF – if autoimmune disease expected

• ESR – if autoimmune disease expected; probably not great for inpatient workup

• CRP – if autoimmune disease expected; probably not great for inpatient workup

• Flow cytometry for LGL

• Bone marrow biopsy – mainly for unexplained neutropenia to rule out neoplastic process, such as leukemia, lymphoma, myeloma; if longstanding, likely negative

Management:

• Treat the underlying cause

• Autoimmune neutropenia –

  • When to suspect? Workup is negative, but their counts still continue to worsen

  • Treatment if they have serious complications

  • Treat with rituximab

• LGL-

  • Responds to low dose methotrexate or cyclophosphamide

• Do you give G-CSF?

  • For patients with recurrent/severe infections or mucosal erosions

  • Do not treat based on the number alone

  • Takes time for the growth factors to work, so does not provide acute improvements in neutropenia 

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References:

https://doi.org/10.1182/blood-2014-02-482612 - Great “How I Treat” article from Blood!

https://www.uptodate.com/contents/approach-to-the-adult-with-unexplained-neutropenia - UpToDate article written by same author as Blood article